The invention features methods and kits for the treatment of neurogenic inflammation by targeting nociceptors with drugs of low molecular weight, while minimizing effects on non-pain-sensing neurons or other types of cells.
According to the method of the invention, small, hydrophilic drug molecules gain access to the intracellular compartment of pain-sensing neurons via entry through receptor/channels that are present in pain-sensing neurons but to a lesser extent or not at all in other types of neurons or in other types of tissue.
Neurogenic inflammation is a mode of inflammation mediated by the efferent (motor) functions of sensory neurons, in which pro-inflammatory mediator molecules released in the periphery by pain-sensing neurons (nociceptors) both activate a variety of inflammatory pathways and also act on the vascular system to alter blood flow and capillary permeability.
Neurogenic inflammation contributes to the peripheral inflammation elicited by tissue injury, autoimmune disease, infection, exposure to irritants in a variety of tissues, and is thought to play an important role in the pathogenesis of numerous disorders (e.g. migraine, arthritis, rhinitis, gastritis, colitis, cystitis, and sunburn).
One way to reduce neurogenic inflammation is to block excitability in nociceptors, thereby preventing the activation of nociceptor peripheral terminals and the release of pro-inflammatory chemicals. Local anesthetics such as lidocaine and articaine act by inhibiting voltage gated ion channels in neurons. Local anesthetics are relatively hydrophobic molecules that gain access to their blocking site on the sodium channel by diffusing into or through the cell membrane. However, these anesthetics block sodium or calcium channels and thereby the excitability of all neurons, not just pain-sensing neurons. Thus, administration of local anesthetics produces unwanted or deleterious effects such as general numbness from block of low threshold pressure and touch receptors, motor deficits from block of motor axons and other complications from block of autonomic fibers. Local anesthetics also act on sodium channels on smooth muscle in the cardiovascular and respiratory systems producing deleterious effects.
Accordingly, there is a need for an approach to reducing neurogenic inflammation that selectively targets nociceptors.